Uveal melanoma is a malignant neoplasm that arises in the pigmented portions of the eye, specifically in the iris, ciliary body or choroid. Therapy for uveal melanoma includes local therapy with enucleation or brachytherapy. Approximately half of patients develop metastatic disease, typically to the liver and often to lung and bone, and the incidence of new metastases continues to increase with time suggesting that the disease is slow growing. The outcome for patients with metastatic disease is dismal. No therapy for this disease has been approved to date.
Mutations affecting either one of two genes that encode G protein alpha subunits of heterotrimeric G protein complexes (GNAQ and GNA11) were discovered in the vast majority of tumors (Van Raamsdonk C D, Bezrookove V, Green G, et al, Nature (2009); 457:599-601 and Van Raamsdonk C D, Griewank K G, et al (2010), N Eng J Med; 363:2191-9). The mutations identified are typical of activating mutations affecting other G proteins.
In spite of numerous treatment options for patients with cancer, there remains a need for effective and safe therapeutic agents and a need for new combination therapies that can be administered for the effective long-term treatment of cancer.
The present inventors have now found that inhibition of the signaling cascade downstream of these G proteins may be useful for the treatment of a proliferative disease such as cancer, e.g. a tumor with a Ga mutation (GNA11/GNAQ), and in particular, uveal melanoma, metastatic uveal melanoma, and GNAQ or GNA11 mutant uveal melanoma.
It has now been found that a combination of a protein kinase C (PKC) inhibitor compound and a MEK inhibitor compound is effective for the delay of progression or treatment of a proliferative disease, especially uveal melanoma, metastatic uveal melanoma, and GNAQ or GNA11 mutant uveal melanoma.
It has now been surprisingly discovered that the combination of an effective amount of a protein kinase C (PKC) inhibitor, e.g. 3-(1H-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-1H-pyrrole-2,5-dione, or a pharmaceutically acceptable salt thereof, e.g. the acetate thereof, with an effective amount of at least one MEK inhibitor compound, e.g. 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethoxy)-amide or (S)-5-fluoro-2-(2-fluoro-4-(methylthio)phenylamino)-N-(2-hydroxypropoxy)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide, more preferably, 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethoxy)-amide, results in unexpected improvement in the treatment of proliferative diseases, particularly cancer, and more particularly uveal melanoma, metastatic uveal melanoma, and GNAQ or GNA11 mutant uveal melanoma.
When administered simultaneously, sequentially or separately, the preferred protein kinase C (PKC) inhibitor compound and the preferred MEK inhibitor compound interact in a synergistic manner to strongly inhibit cell proliferation and are surprisingly efficacious in uveal melanoma models This unexpected synergistic reaction allows reduction in the dose required for each compound, leading to a reduction in the side effects and enhancement of the long-term clinical effectiveness of the compounds in treatment.